The Denver Autoimmunity Center of Excellence encompasses a wide array of clinical investigators involved in studies of autoimmune diseases. The Denver ACE includes groups doing clinical investigation on type 1 diabetes, systemic lupus erythematosus and lupus nephritis, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, autoimmune pulmonary diseases including interstitial lung disease and granulomatous lung disease, celiac disease, inflammatory bowel diseases, autoimmune polyendocrine syndromes and Addison's disease, and autoimmune skin diseases including vitiligo, pemphigus, and lupus-related rashes. These disease groups, involving multiple clinical specialties, departments, and institutions are part of the Denver ACE and have pledged their interest and support. In the original application and this renewal application, diseases being studied in individual clinical projects have included type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, Addison's disease and autoimmune polyendocrine syndromes, celiac disease, and vitiligo. Among the different clinical components of the Denver ACE is the Barbara Davis Center for Childhood Diabetes, which is well known for its role in innovative research in the treatment and prevention of type 1 diabetes. The Denver ACE also includes a number of groups interested in the investigation of systemic lupus and two large Centers of multiple sclerosis patients. An important addition to the current renewal application is the addition of the rheumatology group at the University of Nebraska Medical Center and the Rheumatoid Arthritis Investigational Network (RAIN) of clinical rheumatologists and other personnel directed to the study of RA. In the preceding funding period, the Denver ACE has been involved in the design of clinical trials investigating the use of parenteral insulin for the prevention of islet cell autoimmunity and type 1 diabetes in high risk children, the use of a monoclonal antibody to complement component C5 in the treatment of lupus nephritis, and the use of mycophenolate with daclizumab in new onset type 1 diabetes. The Denver Center is also a collaborating site for ACE studies of anti-CD20 in systemic lupus. Two novel Phase II randomized, double-blind, and placebo-controlled protocols are included in the current renewal application. The first investigates the use of an insulin peptide B9-23 altered peptide ligand to prevent development of disease in patients with prediabetes. The second involves the use of a monoclonal antibody to CD20 (rituximab) in the treatment of patients with early (recent-onset) rheumatoid arthritis. Both trials will also involve considerable mechanistic studies.